The metastatic progression of breast cancer is caused by the aberrant-expression of multiple different genes. We will test the overall hypothesis that breast cancer can be treated more effectively by coordinately correcting linked-genetic errors required for its metastatic progression. We have shown that FKBP/38 and Id- 1 gene sets play significant roles in metastatic progression. Our multi-cassette vectors can efficiently express multiple different genes in tumor-bearing mice. We propose to use systemic transfer of FKBPr38- and ld-1- linked genes to more effectively block the metastatic progression of murine (4T1) and of human (MDA-MB- 231) breast carcinomas in mice. To achieve these goals we will conduct experiments summarized in our three specific aims. Aim 1. To assess the effects of systemic expression of the FKBPK38, or ld-2 genes, and of systemic, targeting of the ld-1,MMP-9 or MT1-MMP genes on the metastatic progression of breast carcinomas in mice. Aim 1 will measure the anti-metastatic activities of each of these genes or anti-genes when administered individually in mice bearing mice well-established metastases, as well as assess target gene modulation at three different time points. Aim 2: To identify combinations of FKBPK38- or ld-1-linked genes that maximally suppress the metastatic progression of breast cancers in tumor-bearing mice. This aim will measure metastatic progression in conjunction with tumor angiogenesis, proliferation and/or apoptosis in order to test the following hypotheses: Metastatic breast cancers, since they are caused by multi-genie abnormalities, will be more effectively be treated by combinations of linked anti-tumor genes. Aim 3: To determine whether effective anti-tumor gene(s) and/or anti-gene(s) act primarily within tumor cells, or act within the tumor microenvironment as well. This aim will test the hypothesis that some effective anti- metastatic genes or anti-genes act primarily within tumor cells, whereas others produce their effects, at least in part, by altering gene expression within the tumor microenvironment. In summary, we will attempt to identify combinations of linked anti-tumor genes and anti-genes that can more effectively block the metastatic progression of breast cancers than mono-genie interventions. The most effective combinations can be specifically targeted by emerging small molecule-, protein- and gene-based therapeutic approaches.